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A '''migraine prophylactic''' is a medicine taken on a regular schedule to reduce the frequency, severity, or duration of [[wikipedia:Migraine|migraine]] attacks, rather than to treat an attack once begun. The category sits in contrast to the [[:Category:Triptans|triptans]] and the newer gepant and ditan abortive medicines used to terminate an established attack. The prophylactic indication is offered to patients with frequent, severe, prolonged, or difficult-to-abort migraines, or to patients in whom abortive therapy is contraindicated or inadequate; the conventional threshold for offering prophylaxis is approximately four migraine days per month, although the clinical judgment is individual.

The prophylactic pharmacopoeia is unusual in that its medicines were, until 2018, all discovered to work on migraine prevention as a side observation of their primary indication, rather than designed for the purpose. The first effective prophylactic was the beta-blocker [[wikipedia:Propranolol|propranolol]], reported by [[wikipedia:James Black (pharmacologist)|James Black]]'s collaborators in the late 1960s to reduce migraine frequency in patients taking the medicine for angina or hypertension;<ref name="rabkin1966">Rabkin R, Stables DP, Levin NW, Suzman MM. The prophylactic value of propranolol in angina pectoris. ''American Journal of Cardiology''. 1966 Sep;18(3):370-383. PMID 5919589.</ref> the randomised trials in the 1970s established the benefit and the indication. Several other beta-blockers (metoprolol, atenolol, nadolol, timolol) have similar efficacy; the lipophilic and central-nervous-system-penetrating beta-blockers (propranolol, metoprolol) seem somewhat more effective than the hydrophilic atenolol, but the clinical difference is small.

The tricyclic antidepressant [[wikipedia:Amitriptyline|amitriptyline]] entered the migraine-prophylaxis category by a similar route: clinical observation that depressed patients taking the medicine had fewer migraines than expected. The 1965 Woodforde report of amitriptyline efficacy in trigeminal neuralgia and the subsequent Couch reports of migraine benefit established the dose range (10 to 75 mg at bedtime, well below the antidepressant dose) and the side-effect-mediated dose ceiling. Nortriptyline, with somewhat less anticholinergic effect, is the contemporary tricyclic of choice. The selective serotonin reuptake inhibitors have not shown clear prophylactic benefit in randomised trials; the serotonin-noradrenaline reuptake inhibitors [[wikipedia:Venlafaxine|venlafaxine]] and [[wikipedia:Duloxetine|duloxetine]] have modest benefit and are sometimes used.

The anticonvulsants entered the category in the 1990s. [[wikipedia:Topiramate|Topiramate]] (Janssen, originally for epilepsy 1996, migraine-prophylaxis indication 2004) reduces migraine frequency by approximately 50 percent in responders and is one of the most-prescribed migraine prophylactics in current U.S. practice; its dose-limiting cognitive effects, paraesthesia, weight loss, kidney-stone formation, and metabolic acidosis have limited adherence. [[wikipedia:Divalproex|Divalproex sodium]] (valproate, Abbott 1996) has comparable efficacy but its teratogenicity (neural-tube defects, autism-spectrum and cognitive effects on prenatal exposure) has restricted its use in women of childbearing age. [[wikipedia:Gabapentin|Gabapentin]] has uncertain efficacy in randomised trials and is not first-line.

The calcium channel blocker [[wikipedia:Flunarizine|flunarizine]] (Janssen 1979, not approved in the U.S. but widely used in Europe) is an effective prophylactic in adults and is the first-line prophylactic in paediatric migraine in several European guidelines. [[wikipedia:Verapamil|Verapamil]], although better-known for its other cardiac uses, is the standard prophylactic for cluster headache rather than migraine.

The transformative event of contemporary migraine prophylaxis was the development of medicines targeting the [[wikipedia:Calcitonin gene-related peptide|calcitonin gene-related peptide]] (CGRP) pathway. CGRP, identified in 1982 by Steven Rosenfeld and Michael Rosenfeld at the Salk Institute as a peptide encoded by alternative splicing of the calcitonin gene, was shown in the 1990s by [[wikipedia:Lars Edvinsson|Lars Edvinsson]] and [[wikipedia:Peter Goadsby|Peter Goadsby]] to be released during migraine attacks and to mediate the dilation and inflammation of cranial vessels and meninges. The monoclonal antibodies [[wikipedia:Erenumab|erenumab]] (Amgen/Novartis, 2018, targeting the CGRP receptor) and [[wikipedia:Galcanezumab|galcanezumab]] (Eli Lilly, 2018), [[wikipedia:Fremanezumab|fremanezumab]] (Teva, 2018), and [[wikipedia:Eptinezumab|eptinezumab]] (Lundbeck, 2020, intravenous quarterly) targeting the CGRP ligand were the first migraine-specific prophylactic medicines.<ref name="goadsby2017">Goadsby PJ, Reuter U, Hallström Y, Broessner G, Bonner JH, Zhang F, Sapra S, Picard H, Mikol DD, Lenz RA. A controlled trial of erenumab for episodic migraine. ''New England Journal of Medicine''. 2017 Nov 30;377(22):2123-2132. PMID 29171821.</ref> The randomised trials demonstrated 50-percent reduction in monthly migraine days in approximately half of treated patients, with comparable benefit in chronic and episodic migraine and a benign safety profile distinct from any earlier prophylactic. The class has become the standard second-line prophylactic in patients who fail conventional medicines, and is moving toward first-line in selected populations.

The small-molecule gepants [[wikipedia:Rimegepant|rimegepant]] (Biohaven 2020 abortive, 2021 prophylactic) and [[wikipedia:Atogepant|atogepant]] (AbbVie 2021) are oral CGRP-receptor antagonists used as daily prophylactics; rimegepant is unique in having both abortive and prophylactic indications. The 5-HT1F-receptor agonist [[wikipedia:Lasmiditan|lasmiditan]] is abortive only. [[wikipedia:OnabotulinumtoxinA|OnabotulinumtoxinA]] (Botox) was approved in 2010 for chronic migraine (15 or more migraine days per month) on the basis of the PREEMPT trials; the medicine is administered as 155 to 195 units divided across 31 to 39 head-and-neck injection sites every twelve weeks. Devices (single-pulse transcranial magnetic stimulation, supraorbital transcutaneous nerve stimulation, vagus nerve stimulation, remote electrical neuromodulation) and the small but growing role of nutraceuticals (riboflavin 400 mg daily, coenzyme Q10, magnesium, butterbur with caution for hepatotoxicity) complete the contemporary prophylactic toolkit.

The contemporary clinical approach to migraine prophylaxis is to escalate from conventional first-line medicines (a beta-blocker if not contraindicated; a tricyclic; topiramate) through the second-line ones (a calcium channel blocker; the SNRIs; divalproex in patients not of childbearing potential), with the CGRP-pathway medicines either as third-line after two prior failures or as first-line in patients with contraindications to or specific intolerance of the conventional medicines. The 50-percent-reduction benchmark for response, applied at 8 to 12 weeks for the conventional medicines and at 12 to 24 weeks for the CGRP monoclonals, defines treatment success and informs the duration of a continued trial.

== Classes indexed ==

By mechanism:

* '''Beta-blockers''' (cross-indexed under [[:Category:Beta-blockers|beta-blockers]]; the conventional first-line):
** [[wikipedia:Propranolol|Propranolol]], metoprolol, atenolol, nadolol, timolol
* '''Antidepressants''' (cross-indexed; modest evidence, often combined with other prophylactics):
** Tricyclics: [[wikipedia:Amitriptyline|amitriptyline]], nortriptyline
** SNRIs: [[wikipedia:Venlafaxine|venlafaxine]], duloxetine
* '''Anticonvulsants''':
** [[wikipedia:Topiramate|Topiramate]] (the most-used conventional prophylactic in current U.S. practice)
** [[wikipedia:Divalproex|Divalproex sodium]] (teratogenicity-limited in women of childbearing age)
** [[wikipedia:Gabapentin|Gabapentin]], pregabalin (limited evidence)
* '''Calcium channel blockers''':
** [[wikipedia:Flunarizine|Flunarizine]] (Europe, paediatric first-line in selected guidelines)
** [[wikipedia:Verapamil|Verapamil]] (for cluster headache rather than migraine)
* '''[[wikipedia:Calcitonin gene-related peptide|CGRP]]-pathway monoclonals''' (parenteral, once-monthly or quarterly):
** Receptor antagonist: [[wikipedia:Erenumab|erenumab]]
** Ligand antagonists: [[wikipedia:Galcanezumab|galcanezumab]], [[wikipedia:Fremanezumab|fremanezumab]], [[wikipedia:Eptinezumab|eptinezumab]]
* '''Oral CGRP-receptor antagonists (gepants)''' (also indexed under abortive medicines for rimegepant and zavegepant):
** [[wikipedia:Rimegepant|Rimegepant]] (abortive + prophylactic)
** [[wikipedia:Atogepant|Atogepant]] (prophylactic only)
* '''[[:Category:Botulinum_toxin|OnabotulinumtoxinA]]''' (Botox) for chronic migraine, PREEMPT-trial-based dosing
* '''Nutraceuticals''' (limited evidence, low-cost adjuncts):
** Riboflavin (B2, 400 mg daily), coenzyme Q10 (100 mg three times daily), magnesium oxide or magnesium citrate, butterbur (''Petasites hybridus'' extract, caution for hepatotoxicity)

== Notes on scope ==

The boundary of this category is "medicine prescribed regularly for the prevention of migraine attacks." The abortive medicines used to terminate an active attack (the [[:Category:Triptans|triptans]], the gepants in their acute-treatment use, [[wikipedia:Lasmiditan|lasmiditan]], NSAIDs, ergot derivatives, antiemetics with analgesic effect, intranasal lidocaine) are listed under [[:Category:Antimigraine_agents|antimigraine agents]] separately. The medicines used for cluster headache prophylaxis (verapamil, the CGRP monoclonals at higher doses, lithium, melatonin, oral or injectable corticosteroid bridging during a cluster) are sometimes treated alongside migraine prophylaxis but are clinically distinct and are referenced on the respective medicine pages. The non-pharmacological interventions (lifestyle modification, identification of migraine triggers, biofeedback, cognitive-behavioural therapy, acupuncture in selected guidelines, the [[wikipedia:Migraine surgery|surgical decompression of nerve-entrapment sites]] in selected refractory patients) are not medicines and are referenced for clinical-decision context only.

== About these pages ==

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.

== References ==

<references/>

[[Category:Medicines]]
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Category:Migraine prophylaxis - Revision history

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